CN103254269A - A,B-cyclobilactam steroid compound and synthetic method thereof and application A,B-cyclobilactam steroid compound of in preparing antitumor drugs - Google Patents
A,B-cyclobilactam steroid compound and synthetic method thereof and application A,B-cyclobilactam steroid compound of in preparing antitumor drugs Download PDFInfo
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Abstract
The invention discloses a A,B-cyclobilactam steroid compound with a chemical formula as shown in the subscription. According to the experiments, the A,B-cyclobilactam steroid compound disclosed by the invention is proved to have a remarkable inhibition effect to a plurality of tumor cell strains, and can be applied in preparing the drugs for treating cancers.
Description
One, technical field
The present invention relates to a class A, the two lactan steroidal compounds of B-ring and synthetic method thereof, with and application in the preparation antitumor drug.
Two, background technology
Cancer (medically the malignant tumour that derives from epithelium being called cancer) is to one of human health and the dangerous maximum disease of quality of life.Seeking efficient, highly selective and the little cancer therapy drug of side effect is the main direction of PTS exploitation.In the research of antitumor drug, once reported courage steroid-4-alkene-B cyclic lactam compound (Natalija M.
MiraS.Bielakovi á,
Synthesis of some steroidal oximes, lactams, thiolactams and theirantitumor activities, Steroids, 2007,72:406 – 414), androstane-B cyclic lactam compounds (Anna I.Koutsourea, Mandis A.Fthanasios Papageorgiou, George N Pairas Papagerous, George N.Pairas, Sotiris S.Nikolaropoulos.Bioorganic﹠amp; Medical Chemistry, 2008,16,5207-5212), androstane D cyclic lactam compounds (Dimitrios T.P.Trafalis, George D.Geromichalos, Catherine Koukoulitsa, AthannasiosPapageorogiou, Panagiotis Karamanakos, Charalambos Camoutsis.Breast Cancer Reaearch andTreatment, 2006,97:17-31).In the above-claimed cpd some has cytotoxicity external to some tumour cell.We once provided a class " 6-replacement-4-azepine-A-homo-3-oxo steroidal compounds and the application in the preparation antitumor drug thereof " patent of invention (Chinese invention patent, ZL201010107528.0) and another kind of " 3-replacements-B-Homo-steroidal-B-cyclic lactam compound and preparation method thereof and the application in preparing antitumor drug " (Chinese patent application number: application for a patent for invention 201110009124.2.).But, on steroidal A-ring and B-ring, form the rarely seen report of two lactan steroidal compounds of lactan simultaneously.Vinod Dave had once reported the preparation of compound 1 in the ring expansion research of 3-carbonyl steroidal, but report (the Vinod Dave of this compound physiologically active and concrete synthetic route not in the literary composition, J.B.Stothers, E.W.Warnho.Resolution ofconflicting migratory reports in ring expansion of3-keto steroids to oxygen and nitrogen, Can.J.Chem.1980,58,2666-2678).
Three, summary of the invention
The purpose of this invention is to provide a class A, the two lactan steroidal compounds of B-ring.
Another object of the present invention provides the synthetic method of above-claimed cpd.
Further purpose of the present invention provides the application of above-claimed cpd in the preparation antitumor drug.
The present invention is achieved through the following technical solutions above-mentioned purpose:
A of the present invention, the two lactan steroidal compounds structural formulas of B-ring are as follows:
A of the present invention, the two lactan steroidal compounds of B-ring are obtained through chemical improvement and modification by natural steroid compound cholesterol, Stigmasterol and Sitosterol, and this method comprises the steps:
1) the steroidal raw material is oxidized to 4-alkene-3 through PCC, and the 6-diketone with the two key reduction in 4-position, further with 3-position carbonyl or 6-position carbonyl oximate, obtains A-cyclic lactam or B-cyclic lactam intermediate by the Backmenn rearrangement then.
2) the 6-position carbonyl in A-cyclic lactam or the B-cyclic lactam intermediate or 3-position carbonyl are converted to oximido, further Backmenn resets and obtains A, the two lactan steroidal compounds of B-ring.
Preparation A, the two lactan steroidal compounds 4 of B-ring, 6-diaza-A-homo-B-homo-courage steroid-3, the reaction of 7-diketone (1) is as follows:
Reagent and condition: a:PCC/CH
2Cl
2; B:NaBH
4/ CH
3OH; C:Jones/CH
3COCH
3; D:NH
2OHHCl/95%EtOH, 60 ℃; E:THF/SOCl
2; F:NH
2OHHCl/95%EtOH, 60 ℃; G:THF/SOCl
2.
Preparation A, the two lactan steroidal compounds 4 of B-ring, 6-diaza-A-homo-B-homo-beans steroid-3, the reaction of 7-diketone (2) is as follows:
Reagent and condition: a:PCC/CH
2Cl
2; B:NaBH
4/ NiCl
26H
2O, CH
3OH; C:NH
2OHHCl/95%EtOH/NaOAc3H
2O; D:SOCl/THF; E:Jones/CH
3COCH
3; F:NH
2OHHCl/95%EtOH/NaOAc3H
2O; G:THF/SOCl
2.
Preparation A, the two lactan steroidal compounds 4 of B-ring, 6-diaza-A-homo-B-homo-paddy steroid-3, the preparation method of 7-diketone (3) and 2 preparation are similar, only are that the material bean sterol is changed to Sitosterol.
Reagent and condition: a:PCC/CH
2Cl
2; B:NaBH
4/ NiCl
26H
2O, CH
3OH; C:NH
2OHHCl/95%EtOH/NaOAc3H
2O; : SOCl/THF; E:Jones/CH
3COCH
3; F:NH
2OHHCl/95%EtOH/NaOAc3H
2O; G:THF/SOCl
2;
Suppress activity test by cancer cell in vitro and show, A of the present invention, the two lactan steroidal compounds of B-ring have significant inhibitory effect to tumor cell lines such as various tumor cell strains such as liver cancer, cancer of the stomach, cervical cancer, colorectal carcinoma, nasopharyngeal carcinoma.So A of the present invention, the two lactan steroidal compounds of B-ring can be used in preparation treatment cancer drug.
The present invention also provides a kind of medicine that is used for the treatment of cancer, and it contains above-mentioned A, the two lactan steroidal compounds of B-ring and pharmaceutically acceptable auxiliary.This medicine can be made the form of injection, tablet, pill, capsule, suspension agent or emulsion and use, and its route of administration can be oral, or through subcutaneous, vein or intramuscular injection.
Four, embodiment
The invention will be further described by the following examples.
Embodiment 14,6-diaza-A-homo-B-homo-courage steroid-3, the preparation of 7-diketone (1)
Step 1: the preparation of intermediate product (4)
Get cholesterol 1.544g and be dissolved in anhydrous methylene chloride 30mL, add PCC(pyridinium chlorochromate) 5.200g.React 29h under the room temperature, add ether 30mL, filter.Solvent in the pressure reducing and steaming filtrate, residual yellow solid obtains product 41.211g, productive rate 76% by column chromatography for separation.Product structure is through IR, and NMR and MS analyze and determine.
Step 2: the preparation of intermediate product (5-6)
Get courage steroid-4-alkene-3,6-diketone 4200mg is dissolved in the 20mL methyl alcohol, adds NiCl
26H
2O120mg after the dissolving fully, adds NaBH fast
490mg, stopped reaction behind the 20min boils off most of methyl alcohol, adds suitable quantity of water, with ethyl acetate 15mL * 3 extractions, is washed till neutrality, anhydrous sodium sulfate drying.Boil off solvent, thick product obtains product 3 through column chromatography for separation, 6-dihydroxyl cholestane 5, productive rate 81%.Product structure is through IR, and NMR and MS analyze and determine.In addition, obtain a small amount of compound 6 as by product.
Step 3: the preparation of intermediate product (7)
Get intermediate product 4 or 5100mg with about 8mL acetone solution, then reaction flask is placed ice-water bath, maintain the temperature between 0-5 ℃, dropwise add Jones reagent, constantly stir, till solution no longer fades, continue reaction 10min., be neutralized to PH ≈ 7 with saturated sodium bicarbonate, the pressure reducing and steaming solvent is used ethyl acetate extraction, washing, drying, the pressure reducing and steaming solvent.Column chromatography for separation obtains product 785mg, and productive rate is 85%.Product structure is through IR, and NMR and MS analyze and determine.
Step 4: the preparation of intermediate product (8)
Get compound 764mg and place reaction flask, add 95% ethanol 10mL, add sodium acetate trihydrate 22mg down at 60 ℃, after the dissolving, add oxammonium hydrochloride 13mg in batches, after the dissolving fully, about 60 ℃, react.Reaction finishes the back decompression and steams most of ethanol, adds a small amount of distilled water then, produces white precipitate.Use the acetic acid ethyl dissolution solid, and use ethyl acetate extraction, use distilled water, saturated common salt water washing respectively, anhydrous sodium sulfate drying.Filter, decompression steams solvent, obtains white solid.To obtain product 860mg behind this solid purifying, productive rate 90.4%.Product structure is through IR, and NMR and MS analyze and determine.
Step 5:4-azepine-A-homo-courage steroid-3, the preparation of 6-diketone (9)
Get compound 8130mg and add in the reaction flask, use the argon shield reaction system.Add dry THF4mL under the ice bath.Slowly add SOCl
2-THF solution, described SOCl
2-THF solution is with 0.7mL SOCl
2Be dissolved among the THF of 2mL drying, continue 0 ° of C reaction.Reaction adds water termination reaction after finishing, and is neutralized to PH ≈ 7 with ammoniacal liquor.Use CH
2Cl
2Extraction product, washing, drying.The pressure reducing and steaming solvent obtains product 959mg after the solid that obtains is purified, productive rate 45%.Product structure is through IR, and NMR and MS analyze and determine.
The preparation of step 6:4-azepine-A-homo-courage steroid-3-oxo-6-oxime (10)
Get compound 9100mg and be dissolved in the 10mL95% ethanol, be warming up to 55 ℃.Add NaAc.3H
2O34mg, the dissolving back adds NH
2OH.HCl7.4mg keeps 55 ℃ of temperature of reaction.Reaction finishes the most of ethanol of back pressure reducing and steaming, adds suitable quantity of water, uses ethyl acetate extraction, washing, drying, pressure reducing and steaming solvent.Obtain product 1080mg, productive rate 78% after thick product is purified.Product structure is through IR, and NMR and MS analyze and determine.
Step 7:4,6-diaza-A-homo-B-homo-courage steroid-3, the preparation of 7-diketone (1)
Get 118mg compound 10 and add in the reaction flask, use the argon shield reaction system, the THF that adds the 5mL drying makes its dissolving, with 1mL SOCl
2Slowly add in the reaction system, temperature of reaction is controlled at 0 ℃ of stirring reaction.No raw material point behind the reaction 4h adds the distilled water termination reaction in mixture, be neutralized to PH ≈ 7 with ammoniacal liquor.Use dichloromethane extraction, merge organic phase, through washing, saturated common salt washing, anhydrous Na
2SO
4Dry.The pressure reducing and steaming solvent, thick product column chromatography for separation obtains white solid 178mg, productive rate 66%, m.p.292-294 ℃.Product structure is analyzed definite through IR, NMR and MS.
Embodiment 24,6-diaza-A-homo-B-homo-beans steroid-3, the preparation of 7-diketone (2)
Step 1: the preparation of intermediate product (11)
The Stigmasterol of getting 2.540g is dissolved in 100mL CH
2Cl
2After, disposable adding PCC11.046g stirs 48h under the room temperature, the TLC monitoring reaction after do not have raw material point, stopped reaction.Reactant impouring one silica gel short column is used ethyl acetate drip washing, collects liquid and removes solvent under reduced pressure, and column chromatography for separation obtains faint yellow solid product 111.746g, productive rate 67%, m.p.152-154 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 2: the preparation of intermediate product (12)
Get in the methyl alcohol that 500mg compound 11 is dissolved in 40mL, and add a small amount of CH
2Cl
2Hydrotropy, disposable adding 285mg NiCl then
26H
2O, be stirred to fully dissolving after, in 10min, add 149mg NaBH in batches
4, react with the cancellation of 1N hydrochloric acid behind the reaction 5min.The most of methyl alcohol of pressure reducing and steaming, add suitable quantity of water, use ethyl acetate extraction, organic phase is washed to neutrality with distilled water, saturated sodium bicarbonate solution, saturated common salt successively, and anhydrous sodium sulfate drying filters, the pressure reducing and steaming solvent, column chromatography for separation obtains white solid 12191mg, productive rate 38%, m.p142-144 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 3: the preparation of intermediate product (13)
Get 196mg compound 12 and be dissolved in the 20mL95% ethanol, add 60mg NaAc3H
2O, being stirred to fully, the dissolving back adds 39mg NH
2OHHCl, the control temperature of reaction is 60 ℃, reaction 2h, the TLC monitoring reaction, behind the no raw material point, stopped reaction.The most of ethanol of pressure reducing and steaming adds suitable quantity of water, uses ethyl acetate extraction.Organic phase is used distilled water, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous sodium sulfate drying successively.Filter, the pressure reducing and steaming solvent, thick product column chromatography for separation obtains white solid 13167mg, productive rate 83%, m.p.197-199 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 4: the preparation of intermediate product (14)
Get 440mg compound 13 and add in the reaction flask, use the argon shield reaction system, add the 16mL dry THF and make its dissolving, again with 5mL SOCl
2Slowly add in the reaction system, at 0 ℃ of stirring reaction.No raw material point behind the reaction 4h adds the suitable quantity of water termination reaction in mixture, be neutralized to PH ≈ 7 with ammoniacal liquor.Use dichloromethane extraction, merge organic phase, through washing, saturated common salt washing, anhydrous Na
2SO
4Dry.The pressure reducing and steaming solvent, thick product column chromatography for separation obtains white solid 14328mg, productive rate 75%, m.p.253-255 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 5: the preparation of intermediate product (15)
Get 261mg compound 14 and be dissolved in the 50mL methylene dichloride, disposable adding 968mg chromium trioxide pyridine reacts under the room temperature, no raw material point behind the reaction 6h.Filter fast, filtrate adds 1mol/L HCl and transfers to PH ≈ 7, uses distilled water, saturated NaHCO respectively
3Solution, saturated common salt water washing, anhydrous Na
2SO
4Dry.Pressure reducing and steaming solvent, column chromatography for separation obtain white solid 15148mg, productive rate 58%, m.p.227-229 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 6: the preparation of intermediate product (16)
Get compound 15109mg and place reaction flask, add 95% ethanol 20mL, add sodium acetate trihydrate 30mg then, after the dissolving, slowly add oxammonium hydrochloride 27mg, the control temperature of reaction is about 60 ℃, no raw material point behind the reaction 1h, most of ethanol is removed in decompression, adds a little distilled water, use dichloromethane extraction, merge organic layer.Organic layer is respectively with distilled water, saturated common salt washing, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, column chromatography for separation obtain compound 1681mg, productive rate: 72%, m.p.260-263 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 7:4,6-diaza-A-homo-B-homo-beans steroid-3, the preparation of 7-diketone (2)
232mg compound 16 is added in the reaction flask, use the argon shield reaction system, add the 6mL dry THF and make its dissolving.With 3mL SOCl
2Slowly add in the reaction system, the control temperature of reaction is at 0 ℃.No raw material point behind the reaction 4h adds freezing distilled water termination reaction in mixture, be neutralized to PH ≈ 7 with ammoniacal liquor.Use CH
2Cl
2Extraction merges organic phase, through saturated NaHCO
3Solution is washed, saturated common salt washing, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, thick product column chromatography for separation obtains white solid product 268mg, productive rate 30%, m.p.236-239 ℃.Product structure is analyzed definite through IR, NMR and MS.
Embodiment 34,6-diaza-A-homo-B-homo-paddy steroid-3, the preparation of 7-diketone (3)
Step 1: the preparation of intermediate product (17)
Synthetic method is synthetic identical with compound 11, and raw material is Sitosterol, obtains faint yellow solid 17, productive rate 80%, m.p.173-175 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 2: the preparation of intermediate product (18)
Synthetic method is synthetic identical with compound 12, and raw material is compound 17, obtains white solid 18, productive rate 43%, m.p.137-139 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 3: the preparation of intermediate product (19)
Synthetic method is synthetic identical with compound 13, and raw material is compound 18, obtains white solid 19, productive rate 83%, m.p.216-218 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 4: the preparation of intermediate product (20)
Synthetic method is synthetic identical with compound 14, and raw material is compound 19, obtains white solid 20, productive rate 72%, m.p.274-276 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 5: the preparation of intermediate product (21)
Synthetic method is synthetic identical with compound 15, and raw material is compound 20, obtains white solid 21, productive rate 65%, m.p.205-207 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 6: the preparation of intermediate product (22)
Synthetic method is synthetic identical with compound 16, and raw material is compound 21, obtains white solid 22, productive rate 73%, m.p.266-268 ℃.Product structure is analyzed definite through IR, NMR and MS.
Step 7:4,6-diaza-A-homo-B-homo-paddy steroid-3, the preparation of 7-diketone (3)
Synthetic method is synthetic identical with compound 2, and raw material is compound 22, obtains white solid 3, productive rate 34%, m.p.279-282 ℃.Product structure is analyzed definite through IR, NMR and MS.
Embodiment 4
Present embodiment is to adopt A of the present invention, and the two lactan steroidal compounds of B-ring carry out the test result of cell toxicity test to some tumour cell.
Adopt the MTT method, to A of the present invention, the two lactan steroidal compounds of B-ring carry out growth and proliferation of cell to human stomach cancer cell line (SGC-7901), human nasopharyngeal epithelioma 1 (CNE), hepatoma cell strain (Bel-7404), cervical cancer cell strain (HeLa), colon cancer cell line (HT-29) and suppress activity test.The A that adds different concns in the logarithmic phase cell of in 96 orifice plates, cultivating, the two lactan steroidal compounds of B-ring, carry out 3 parallel tests simultaneously, compare with control group, cultivate after 72 hours, add MTT, measure its absorbancy, calculate respectively and suppress growth of tumour cell to 50% o'clock compound concentrations, with IC
50Value representation, the result is as shown in table 1:
External antiproliferative activity (the IC of the two lactam compound 1-3 of table 1AB ring
50, μ mol/L)
| Compound | SGC-7901 | CNE | Bel-7404 | HeLa | HT-29 |
| 1 | 11.6 | 16.2 | 16.4 | 13.9 | 44.2 |
| 2 | nd | nd | >80 | 17.5 | >80 |
| 3 | nd | nd | 21.8 | 13.1 | nd |
Nd: do not measure.
From table data as seen, this type of A, the two lactan steroidal compounds of B-ring have the obvious growth inhibited proliferation to some tumour cell wherein.
Claims (4)
1. A, the two lactan steroidal compounds of B-ring, chemical structural formula is as follows:
2. one kind prepares the described A of claim 1, and the method for the two lactan steroidal compounds of B-ring is characterized in that, obtained through chemical improvement and modification by natural steroid compound cholesterol, Stigmasterol and Sitosterol, concrete steps are as follows:
1) the steroidal raw material is oxidized to 4-alkene-3 through PCC, and the 6-diketone with the two key reduction in 4-position, further with 3-position carbonyl or 6-position carbonyl oximate, obtains A-cyclic lactam or B-cyclic lactam intermediate by the Backmenn rearrangement then,
2) the 6-position carbonyl in A-cyclic lactam or the B-cyclic lactam intermediate or 3-position carbonyl are converted to oximido, further Backmenn resets and obtains A, the two lactan steroidal compounds of B-ring.
3. A as claimed in claim 1, the application of the two lactan steroidal compounds of B-ring in the preparation antitumor drug.
4. A as claimed in claim 1, the application of medicinal compositions in the preparation antitumor drug that the two lactan steroidal compounds of B-ring are activeconstituents.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800580A (en) * | 2017-01-12 | 2017-06-06 | 中国药科大学 | Sterol derivative and its preparation method and application |
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| CN102146115A (en) * | 2011-01-17 | 2011-08-10 | 广西师范学院 | 3-substituent-B-Homo-steride-B-cyclolactam compound as well as preparation method and application to preparing antitumor medicaments |
| CN103012540A (en) * | 2013-01-06 | 2013-04-03 | 广西师范学院 | 22-drop-6-hydroxystigmast-3,22-O-dimethyloxime ether and 22-drop-6-oximido-stigmast-3,22-O-dimethyloxime ether and application thereof to preparation of antitumor drugs |
-
2013
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| JPH1072487A (en) * | 1996-09-03 | 1998-03-17 | Taisho Pharmaceut Co Ltd | Sterol compound |
| CN102146115A (en) * | 2011-01-17 | 2011-08-10 | 广西师范学院 | 3-substituent-B-Homo-steride-B-cyclolactam compound as well as preparation method and application to preparing antitumor medicaments |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106800580A (en) * | 2017-01-12 | 2017-06-06 | 中国药科大学 | Sterol derivative and its preparation method and application |
| CN106800580B (en) * | 2017-01-12 | 2019-05-10 | 中国药科大学 | Sterol derivative and its preparation method and application |
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Application publication date: 20130821 |